Loss of the key protein Smad3 in the pathway that regulates proliferation of T-cells appears to be specific to childhood acute T-cell leukemia, according to an article in the August 5th issue of the New England Journal of Medicine. The findings give new insight into molecular distinctions among different forms of leukemia.

Smad3 is important in a cellular network relay system called the transforming growth factor B (TGF-B) signaling cascade. TGF-B binds to receptors on the surface of white cell progenitors in bone marrow and activates a multi-protein cascade that relays external signals into the nucleus of the cell. The signals typically slow the rate at which white cells proliferate. Thus, when the signal pathway is interrupted, TGF-B can no longer control cell proliferation and the potential for pathogenesis of leukemia exists.

To better understand the role of Smad3 and how it may vary in different forms of leukemia, John Letterio, MD, and colleagues looked for the presence of Smad3 protein in samples of human leukemia cells collected from patients with one of three different childhood leukemias: a T-cell derived leukemia, B-cell derived leukemia, and non-lymphocytic leukemia.

Smad3 protein was present in the B-cell and non-lymphocyte samples, but almost non-existent in all the T-cell samples. This lack of Smad3 protein appears to be restricted to childhood T-cell leukemia because the researchers demonstrated that Smad3 was present in two adult forms of T-cell leukemia: Sezary syndrome and a virus-induced (HTLV- 1) leukemia.

In mice, deletion of one or both copies of the Smad3 gene specifically impairs the ability of TGF-B to stop T-cell proliferation, so the discovery that Smad3 was unique to the T-cell leukemia was not surprising. The surprise - and mystery - of these findings is the biology behind Smad3's absence. The leukemia cells produced normal levels of Smad3 mRNA. Furthermore, researchers found that the sequence of the Smad3 gene in patient samples was identical to the normal Smad3 gene found in healthy T cells, signifying that a genetic mutation was not the cause.

"We don't yet know the mechanisms behind this loss of Smad3 protein," said Letterio, "but two possibilities may be that protein synthesis is being blocked or that the protein is made but degraded very quickly."

Smad3 loss alone is likely not responsible for onset of leukemia because Smad3-deficient mice do not develop tumors despite their increased number of T-cells. To address the hypothesis that another factor is required, Letterio's group examined the connection between Smad3 and p27Kip1, another protein with an important role in regulating cell growth. Mice with p27Kip1 deleted have increased numbers of T-cells but, similar to mice with Smad3 deleted, they do not develop leukemia.

However, when the researchers deleted one copy of the Smad3 gene in p27Kip1-deficient mice, 50 percent of the mice died within six months, and several of them developed leukemia. Mice with both p27Kip1 and Smad3 completely deleted could not be studied because of the high prevalence of embryonic death.

The researchers hope that continued work will uncover other genetic alterations that, when linked with Smad3 loss, play a role in the genesis of pediatric T-cell leukemia.

Letterio also pointed out that their study did not examine all the variations of leukemia. "Whether or not Smad3 plays a role in other forms of leukemia is still an open question," he said.